The generation of molecularly engineered animal models has provided invaluable insight into the pathogenesis of human diseases. The long-term objective of this proposal is to establish a novel mouse model system to study the pathogenesis and mechanism of potential human diseases caused by the loss or disruption of the target novel protein NIBP (NIK and IKK2-binding protein). Limited new clinical data have identified the importance of NIBP in a few human diseases including autosomal recessive mental retardation, autism, hearing loss, stroke, etc. These clinical findings highlight the importance of NIBP in neurogenesis, mental development, and cognitive behavior. However, the underlying cause-effect relationships and mechanisms remain unknown. NIBP enhances cytokine-induced activation of NF:B, a major mediator for inflammation, immunity and neural plasticity, and a key player in multiple developmental defects and various chronic diseases such as neurodegenerative diseases, autoimmune, bone loss and cancer. NIBP is also a key member of trafficking protein particle (TRAPP) complex II, implying its importance in regulating cellular trafficking. The extensive functions of NIBP in the broad science fields prompted us to generate NIBP conditional knockout mice. In a pilot study using the cre-loxP conditional gene knockout and Red recombineering techniques, we produced floxed NIBP transgenic mice. In aim 1 of this proposal, we will generate universal NIBP knockout mice at different stages of development by crossbreeding floxed NIBP mice with universal and inducible cre mice followed by Tamoxifen induction in embryonic, postnatal (P5-P10), young (1-2 months) and adult (6-8 months) mice. These mice will help us to identify potential disease-related phenotypes and provide extensive topics for further studies. The effect of NIBP knockout on embryonic and adult neurogenesis will be identified. In aim 2, we will generate neuron-specific NIBP knockout mice at different developmental stages by using neuron-specific inducible Cre mice (Neurog1-Cre/ERT). These mice will be ideal models to test a novel hypothesis that NIBP preferentially guides neuronal lineage development and maintains mature neuronal functions. Mutual interaction between NIBP and Neurogenin1 in neural stem/progenitor cells will be investigated. Phenotypic analysis of these conditional NIBP knockout mice will identify potential disease-related syndromes. Project narrative: The outcome of the proposed studies will conclusively address the functions and mechanisms of NIBP in multiple systems and human diseases such as mental retardation. The successful accomplishment of this project will provide new clues for human diseases or syndromes and substantially increase our knowledge of NF:B signaling and protein trafficking in the most prevalent chronic diseases. These mice will be applicable to the research interests of multiple NIH institutes/centers.